Chronic nonmalignant pain is highly prevalent, and is associated with substantial personal suffering, lost productivity, and healthcare costs. Use of opioid analgesics for management of nonmalignant chronic pain has increased dramatically, yet is fraught with controversy due to associated side effects and abuse potential. Moreover, the analgesic efficacy of opioid analgesics can vary widely between individuals. Given the increasing use of opioid analgesics for the management of chronic pain, we aim in this project to improve understanding of factors that influence opioid analgesic effectiveness, and which may have relevance to understanding opioid risks. Possible predictors of individual differences in responses to opioid analgesics include traits of negative affect and emotion regulation, sex, experimental acute pain sensitivity, circulating levels of the endogenous opioid agonist beta-endorphin (BE), and efficiency of conditioned pain modulation (CPM). A common mechanism that may explain how these diverse factors could all predict opioid analgesic responses is endogenous opioid system function. We propose that traits of negative affect and emotion regulation, sex, acute pain sensitivity, plasma BE levels, and CPM may reveal direct effects on opioid analgesic responses, but may also exert influence indirectly via associations with functioning of endogenous opioid antinociceptive systems. We will use controlled laboratory methods to assess acute pain responses in 120 chronic low back pain (LBP) patients and 120 healthy controls across three sessions using a randomized, counterbalanced design: under placebo, opioid blockade (naloxone), and opioid agonist (morphine). Aim1 is to determine the degree to which an index of endogenous opioid function (opioid blockade effects on pain responses) is related to exogenous opioid analgesic effects, and to compare these associations in LBP patients to those shown in healthy people. This will be an innovative test of the hypothesis that better endogenous opioid function (larger opioid blockade effects) predict greater exogenous opioid analgesia. Aim 2 is to determine: a) the degree to which negative affect and emotion regulation traits, sex, acute pain sensitivity, resting plasma BE levels, and CPM are related to exogenous opioid analgesic effects (total effect);and b) the degree to which these factors are related indirectly to exogenous opioid analgesic effects via differences in endogenous opioid function (blockade effects) (mediation). Aim 3 will explore relationships among opioid side effects, indicators of opioid abuse potential, opioid analgesic efficacy, and endogenous opioid function. Results could improve not only theoretical understanding of how these potential markers for poor opioid analgesic response may operate directly versus through a common endogenous opioid mechanism, but eventually permit clinical characterization of likely costs/benefits of opioid-based pain management a priori for a given patient. In addition, results may suggest interventions that could directly target common pain modulatory mechanisms underlying these predictive factors. PUBLIC HEALTH RELEVANCE: Use of opioid analgesics for management of nonmalignant chronic pain has increased, but is fraught with controversy because of risk of abuse, dependence and side effects, and because analgesic efficacy can vary widely between individuals. It is crucial that we identify ways of discriminating patients who will achieve optimal benefit from opioid analgesics from those who may experience few treatment benefits yet still run the risk of side effects. This project will test several potential predictors of poor opioid analgesic responsiveness, and will seek to understand common endogenous opioid mechanisms that may underlie these predictive effects.